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PubMed1991

Collagenase of Clostridium perfringens type A: degradation of human complement component C1q.

The semipurified collagenases from Clostridium perfringens type A strains 2-Cli and ATCC 13124, both characterized by molecular weights of 79.4 kilodaltons, partially degraded purified human complement (C) component C1q. The following purified human serum proteins were refractory: C components C3, C4, C5, C6, C7, C8, and C9; immunoglobulin (Ig)A (from colostrum), IgG, and IgM; alpha 2-macroglobulin, haptoglobin, and C-reactive protein.

Blotting, Western↗
PubMed1998

Human heart generates complement proteins that are upregulated and activated after myocardial infarction.

In human heart, we detected mRNAs and proteins for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 with the use of reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical techniques. We found an upregulation of both mRNAs and proteins in areas of recent and old myocardial infarctions. In both situations, the classical complement pathway was activated, with C4d, C3d, and the membrane attack complex (C5b-9) being deposited on damaged cardiac myocytes. These activated complement components were also identified on Western blots of infarcted tissue. Complement mRNAs in infarcted heart tissue were higher than those in liver, and liver complement mRNAs were not upregulated in cases with infarcted hearts. Our results establish that (1) complement proteins are endogenously produced by human heart; (2) the classical complement pathway is fully activated after myocardial infarction; (3) complement activation is directly involved in myocardial damage after ischemic insults; and (4) damage from complement activation may be chronically sustained. These data suggest that inhibition of the complement system should be effective in treating myocardial infarction.

Adult↗
PubMed1970

Reactive lysis: the complement-mediated lysis of unsensitized cells. II. The characterization of activated reactor as C56 and the participation of C8 and C9.

It has been shown that the "activated reactor" that is produced in certain human sera by complement activation is a stable complex of the fifth and sixth component of complement (C56). On interaction with C7, the indicator factor, a complex C567 is formed which for a short time (half-life less than 1 min) has an activated binding site and can attach itself to normal red cell membranes, conferring on them the hemolytic properties of the "heat stable" complement intermediate EC 1 approximately 7, the capacity to be lysed by C8 and C9. These cells have neither antibody nor the complement components up to C3 bound on them. The binding site-activated C567c-can similarly bind to other hydrophobic surfaces, including agarose gel where it forms a "stainable line". If the complex is not bound to a surface, the binding site decays and the resulting complex will no longer give rise to lysis. However it will still inactivate C8 and C9 in solution. The sera that can generate activated reactor apparently do so because they have an excess of C5 and C6, compared to their content of C7. The phenomenon of reactive lysis thus represents complement-mediated lysis of unsensitized cells initiated at the C5 stage by a stable complex (C56) which was generated by complement activation at a distance. The immunochemistry of the phenomenon is described and some of its implications discussed.

Animals↗
PubMed2001

Mechanism of complement resistance of pathogenic Borrelia burgdorferi isolates.

Borrelia burgdorferi, the causative agent of Lyme disease, differ in their susceptibility to normal human serum and are consequently classified as complement-resistant, complement-sensitive and intermediate complement-sensitive. Most isolates belonging to the genospecies B. afzelii are complement-resistant, while particularly B. garinii isolates were rapidly killed by complement. In general, isolates of the genospecies B. burgdorferi sensu stricto (s.s.) are intermediate complement-sensitive. Independent of the genospecies, all Borreliae were capable to activate the classical and/or the alternative pathway. Deposition of the activation products C3, C6, and TCC is much stronger by B. burgdorferi s.s. and B. garinii isolates than by B. afzelii isolates. The mechanism(s) on how Borreliae evade complement-mediated bacteriolysis has recently been described by showing that complement-resistant B. afzelii isolates but not the complement-sensitive B. garinii isolates absorb human complement regulators FHL-1/reconectin and factor H. Surface-attached FHL-1/reconectin maintains its complement regulatory activity and supports factor I-mediated C3b cleavage to iC3b. In complement-resistant Borreliae, two outer surface proteins, the 27.5 kDa (CRASP-1, complement regulator-acquiring surface protein 1) and the 20/21 kDa (CRASP-2), are responsible for the surface attachment of the two complement regulators. CRASP-1, which is present in complement-resistant Borreliae, binds preferentially FHL-1/reconectin while CRASP-2, which is restrictively expressed, binds preferentially factor H. Thus, complement-resistant Borreliae bind human complement regulators and control complement activation on their surface and prevent the formation of toxic activation products.

Bacterial Outer Membrane Proteins↗
PubMed1975

The serum complement system--a mediator of acute pancreatitis.

The role of the complement system in the initial membrane lesion of acute pancreatitis was investigated. In the experimental sodium-taurocholate pancreatitis of the rat a sudden and steady decline of serum complement was observed. The deposition of C3 component of complement in acute pancreatitis could be demonstrated by immunofluorescence. To rule out mere deposition or activation of complement in the interstitial exsudative fluid, single acinar cells of rat and rabbit pancreatic tissue were prepared and transfered to culture medium. In contrast to heat inactivated serum and C6 deficient serum these cells were lysed by trypsin activated fresh serum. Consequently, an acute pancreatitis could be induced by activating exclusively the complement system by injection of cobra venom factor into the pancreatic duct of rats. The activated complement system is thought to be responsible for initial membrane lesion in exsudative inflammation, as could be shown in acute pancreatitis.

Acute Disease↗
PubMed1998

Neutrophil adhesion to human endothelial cells is induced by the membrane attack complex: the roles of P-selectin and platelet activating factor.

A variety of inflammatory diseases are accompanied by activation of the complement system. We examined the role of the membrane attack complex (MAC) in mediating neutrophil adhesion to endothelial cells. To assemble the MAC in endothelial cell monolayers, a C5b-like molecule was created through the treatment of purified C5 with the oxidizing agent chloramine-T, followed by addition of the remaining components (C6-C9) that constitute the MAC. Use of this method abrogated potentially confounding effects mediated by other complement components (e.g., C5a). MAC assembly resulted in a rapid (30 min), concentration-dependent increase in neutrophil adherence. A monoclonal antibody directed against P-selectin inhibited MAC-mediated neutrophil adhesion. A whole cell EIA confirmed P-selectin expression after formation of the MAC. Incubation of neutrophils with the platelet-activating factor receptor antagonist, CF 3988, also significantly decreased adhesion, indicating that PAF plays a role in MAC-mediated adhesion. These results suggest that the MAC can promote neutrophil adhesion through P-selectin and PAF-mediated mechanisms.

Cell Adhesion↗
PubMed1982

Hemolytic and antigenic measurements of complement. A comparison of serum and plasma samples in normal individuals and patients.

Over a 2-year period we evaluated 10 patients with a discrepancy between functional and antigenic assays in the routinely employed clinical assays for measuring serum complement concentrations. These differences were shown to be secondary to cold-dependent activation of the classical complement pathway in vitro, in some cases by cryoglobulins and in others by unknown means. Plasma samples were procured with commonly used anticoagulants (EDTA, citrate, or heparin) that prevent in vitro complement activation. To assess whether plasma samples were suitable for complement determination, a comparison of serum vs. plasma samples for THC, C4, C2, C3, factor B, and C6 levels in normals and patient populations was undertaken. Only modest differences were found between serum and plasma samples for these functional and antigenic assays except for heparinized samples in which determinations by rate nephelometry produced falsely elevated C4, C3, and factor B antigenic levels. Thus plasma samples, especially EDTA or citrate, are suitable for complement determinations and could be used either routinely or, more selectively, in patients in whom there is a discrepancy between functional and antigenic determinations.

Adult↗
PubMed1987

Complement component deposition in uteroplacental (spiral) arteries in normal human pregnancy.

There is conflicting evidence for the deposition of complement in spiral arteries in normal and abnormal human pregnancies. The immunogold silver staining (IGSS) technique was used to investigate the distribution of C1q, C3d, C4, C6 and C9 within the spiral arteries of formalin-fixed normal pregnancy hysterectomy specimens ranging in gestational age from 4 to 40 weeks. Deposition of complement components studied was observed in all cases suggesting classical pathway activation. Reactivity was not confined to vessels showing endovascular trophoblast though the latter showed a characteristic linear deposition subjacent to the trophoblast. Reactivity was most intense for C3d and C9. An appreciation of complement deposition as a feature of normal pregnancy is essential before significant immunopathology can be recognised in placental bed vessels in abnormal pregnancy.

Antigen-Antibody Reactions↗
PubMed2001

Topological and functional characterization of WbpM, an inner membrane UDP-GlcNAc C6 dehydratase essential for lipopolysaccharide biosynthesis in Pseudomonas aeruginosa.

WbpM is essential for the biosynthesis of B-band lipopolysaccharide (LPS) in many serotypes of Pseudomonas aeruginosa. Homologues that can functionally complement a wbpM null mutant and that are also necessary for virulence have been identified in numerous pathogenic bacteria. WbpM and most of its homologues are large membrane proteins, which has long hampered the elucidation of their biochemical function. This paper describes the detailed characterization of WbpM using both in vivo and in vitro approaches. LacZ and PhoA fusion experiments showed that WbpM was anchored to the inner membrane via four N-terminal transmembrane domains, whereas the C-terminal catalytic domain resided in the cytoplasm. Although the membrane domains did not have any catalytic activity, complementation experiments suggested that they were important for the polymerization of high-molecular-weight B-band LPS. The biochemical characterization of a soluble truncated form of WbpM, His-S262, showed that WbpM was a C6 dehydratase specific for UDP-GlcNAc. It exhibited unusual low temperature (25-30 degrees C) and high pH (pH 10) optima. Although WbpM possessed an altered catalytic triad composed of SMK as opposed to SYK commonly found in other dehydratases, its catalysis was very efficient, with a kcat of 168 min(-1) and a kcat/Km of 58 mM(-1) min(-1). These unusual physico-kinetic properties suggested a potentially different mechanism of C6 dehydration for WbpM and its large homologues. His-S262 is now a precious tool for further structure-function studies.

Bacterial Proteins↗
PubMed1999

Complement membrane attack complex and protectin (CD59) in liver allografts during acute rejection.

BACKGROUND/AIMS: The complement system is important in the rejection of xenografts, but very little is known about its activation in the rejection of allografts. Complement lysis is induced by the membrane attack complex (MAC), an aggregate of C5b, C6, C7, C8 and C9 molecules. The main defender against MAC is the CD59 molecule, also called protectin. In this study, the aim was to analyze the possible deposition of MAC and the fate of CD59 on distinct cell populations during liver allograft rejection. METHODS: Liver allografts were monitored by frequent fine-needle aspiration biopsies (FNAB) to demonstrate the immunoactivation of rejection. To examine MAC and CD59 in the FNAB, in relation to the activation markers of rejection, IL2-receptor, MHC class II and ICAM-1 expression, specific monoclonal antibodies and immunoperoxidase staining were used. RESULTS: Ten out of 21 consecutive liver transplants underwent a histologically confirmed episode of reversible acute rejection. In the FNAB, a significant increase of the activation markers IL2-receptor, class II and ICAM-1 correlated with the peak of inflammation during the episode. In association with inflammation, a significant deposition of MAC was recorded in neutrophils and lymphocytes infiltrating the graft and in the parenchymal cells. MAC deposition subsided together with the inflammation. A significant decrease in CD59 expression was seen in neutrophils during rejection, but CD59 expression on other inflammatory cells and hepatic tissue cells varied greatly. CONCLUSIONS: Complement activation was seen in association with acute rejection of liver allografts and it led to MAC assembly on leukocytes and tissue cells. A decrease in CD59 expression was less clear-cut, but it may predispose the cells to complement-mediated elimination.

Acute Disease↗
PubMed1985

The hereditary and acquired deficiencies of complement.

The identification of hereditary and acquired complement deficiencies in humans has led to a better understanding of the biologic importance of the complement system in immunity and autoimmune disease. Although the understanding of the relevance of complement in the pathogenesis of disease is incomplete, several characteristic clinical syndromes associated with complement deficiencies have been recognized and should be known to the practicing clinician. In allergic diseases, one need recognize the C1 inhibitor deficiency syndromes which can present as severe, recurrent angioedema in childhood or in the adult as recurrent angioedema in association with a lymphoid malignancy or autoimmune disease. Complement analyses allow one to readily diagnose C1 inhibitor deficiency in angioedema. Correct diagnosis is critical because safe effective therapy is available. Chronic urticaria is also uncommonly associated with complement deficiencies, particularly acquired C1q deficiency. Again, effective therapy for hypocomplementemic urticarial vasculitis and C1q deficiency is available and differs significantly from the usual management of chronic urticaria. Homozygous and acquired deficiencies of C3 are associated with severe immune deficiency and recurrent infections with gram-positive and gram-negative bacteria. Recurrent meningococcemia and gonococcemia are being identified frequently in patients with a deficient membrane attack mechanism relating to deficiency of C5, C6, C7, or C8. Nearly one third of the patients developing meningococcemia may have an associated complement deficiency indicating the importance of complement determinations in understanding the treatment and prognosis for these patients. Deficiency of almost every complement component has been reported in association with one or more rheumatic diseases, particularly systemic lupus erythematosus. Extensive studies of C2 deficiency and limited studies of C4 deficiency indicate that these components of the classical pathway of complement are important in preventing the development of SLE or are linked to other genes predisposing to SLE. The clinical presentations of SLE in association with C2 or C4 deficiency are relatively uniform. The patients exhibit typical skin manifestations suggestive of SLE and DLE and often exhibit antibodies to SSA (Ro). The association of complement deficiencies with clinical syndromes is important for today's physician. The syndromes and deficiencies described here are the beginning of an expanding knowledge relating to the pathobiology of complement in human disorders.

Angioedema↗
PubMed1989

Expression of nuclear lamins in mammalian somatic cells lacking cytoplasmic intermediate filament proteins.

Using immunofluorescence and immunoblotting techniques, we have examined the composition of the nuclear lamina in murine plasmacytoma cells, MPC-11, exposed to the phorbol ester TPA as well as in two cell lines devoid of cytoplasmic intermediate filament proteins, the human adrenal cortex carcinoma-derived cells SW-13 and the clone C6-M-D4 derived from the rat glial cell line C6. Our results show that the inhibition of proliferation and the induction of vimentin synthesis observed in TPA-treated MPC-11 populations are not paralleled by changes in the lamin complement of these cells, which contain lamin B but lack lamins A and C. Furthermore, the analysis performed on SW-13 and C6-M-D4 cell lines clearly demonstrates that mammalian somatic cells display considerable variations in lamin expression and indicates that lamin B may be the only lamin species constitutively expressed in mammalian cells.

Adrenal Cortex Neoplasms↗
PubMed1974

Receptor for soluble C3 and C3b on human lymphoblastoid (RAJI) cells. Properties and biologocal significance.

This study describes the presence of a receptor for fluid phase human C3 and C3b on Raji cell membranes. The binding of C3 and C3b was demonstrated indirectly by a fluoresceinated anti-C3 serum and directly by using radioiodinated proteins. No other complement proteins or serum factors were needed to mediate binding of C3 and C3b to the receptor. The possibility of enzymatic cleavage of C3 before or after its attachment on the cell membrane was ruled out by the demonstration of antigenically intact C3 on Raji cells. Inhibition and dissociation of Raji cell-EAC1423 rosettes by C3 and C3b indicated that both of these proteins bind to the same receptor site or closely associated receptor sites on Raji cells. C3b-bearing Raji cells were immune adherence negative, indicating that C3b binding to the receptor is brought about through the immune adherence region of the molecule and not the C3d portion. The C3 receptor on Raji cell membranes is uniformly distributed and can move on the membrane plane. Approximately 4 x 10(5) molecules of C3 or C3b bind per Raji cell. The receptor had a higher affinity for C3 than C3b, as was shown by uptake experiments and inhibition of Raji cell-EAC1423 rosette formation. Apart from the described receptor for C3 and C3b another specific receptor for C3b inactivator-cleaved C3b (C3d) bound to red cells was shown to be present on Raji cells. Raji cells cultured in medium containing fresh normal human serum and cobra venom factor were lysed. Similar results were obtained when C3b-bearing Raji cells were cultured in medium with fresh normal human serum. The lytic effect could be abolished by inactivating serum C3 proactivator (C3PA) and required C6. It was concluded that C3b bound to the Raji cell membrane activates the complement system through the alternate pathway and results in membrane damage and cytolysis. It is postulated that cell destruction by this mechanism may play an important role in vivo in controlling cell growth.

Animals↗
PubMed2000

Synthetic peptides which inhibit the interaction between C1q and immunoglobulin and prolong xenograft survival.

BACKGROUND: Acute vascular xenograft rejection (AVXR), also termed delayed xenograft rejection (DXR), occurs when hyperacute rejection (HAR) is prevented by strategies directed at xenoreactive natural antibodies and/or complement activation. We have hypothesized that AVXR/DXR is initiated in part by early components of the complement cascade, notably C1q. We have developed synthetic peptides (termed CBP2 and WY) that interfere with the interaction between C1q and antibody. METHODS: CBP2 and the WY-conjugates were used as inhibitors of immunoglobulin aggregate binding to solid phase C1q. Inhibition of complement activation by the peptides of the classical system was determined using lysis assays with sensitized sheep red blood cells or porcine aortic endothelial cells as targets and of the alternate complement pathway using guinea pig red blood cells as targets. Two transplant models were used to study the effects of administering peptides to recipients: rat heart transplant to presensitized mouse, and guinea heart transplant to PVG C6-deficient rats. RESULTS: CBP2 and WY-conjugates inhibited immunoglobulin aggregate binding to C1q. The peptides also inhibited human complement-mediated lysis of sensitized sheep red blood cells and porcine aortic endothelial cells in a dose-dependent manner and the WY-conjugates prevented activation of the alternate complement pathway as shown by inhibition of guinea pig red blood cells lysis with human serum. In addition, the use of the peptides and conjugates resulted in significant prolongation of xenograft survival. CONCLUSIONS: The CBP2 and WY peptides exhibit the functional activity of inhibition of complement activation. These peptides also prolong xenograft survival and thus provide reagents for the study of the importance of C1q and other complement components in transplant rejection mechanisms.

Animals↗
PubMed1982

Glutathione-catalyzed disulfide-linking of C9 in the membrane attack complex of complement.

The membrane attack complex of complement (the dimeric C5b-9 complex) is a multimolecular assemblage of five proteins (C5b, C6, C7, C8, and C9) which are held together by noncovalent forces. We found that C9 molecules in the complex can be covalently crosslinked (disulfide-linked) by glutathione. In this experiment, the tetramolecular C5b-8 complex bound to phospholipid vesicles was first prepared from purified C5b-6, incubated (37 degrees C, 20 min) with an excess of 131I-C9 in the presence of 1 mM glutathione; an average of 5.3 molecules of C9 per C5b-8 were bound and the C5b-9 complex formed was predominantly a dimeric C5b-9 complex. About one-third of C9 in this C5b-9 complex was found to be in a disulfide-linked dimeric form. The C5b-9 complex, having only an average of 0.9 molecules of C9 per C5b-8, was also prepared in the presence of glutathione; this C5b-9 preparation contained both monomeric and dimeric C5b-9 complexes, and about one-fifth of the C9 subunits was in a cross-linked dimeric form. By contrast, C9 in the absence of the C5b-8 complex was not significantly cross-linked by glutathione. These results indicate that C9 has a unique property to associate with itself upon reaction with the C5b-8 complex.

Centrifugation, Density Gradient↗
PubMed1984

Effect of different penicillin derivatives on complement components in human serum.

The effect of different penicillin derivatives on the human complement system has been studied in vitro. Four penicillins tested (benzylpenicillin, oxacillin, methicillin, azlocillin) were found to inactivate total hemolytic complement dose dependently. This effect is caused by direct inactivation of C2, C5 and one or more of the components C6-9 as well as by activation of the alternative pathway. At relatively high concentrations, penicillins induce a conformational change in C3 and C4, leading to the C3b-like or C4b-like forms of these molecules, respectively. Prominent effects on the complement system occur at penicillin concentrations exceeding those achieved in plasma under regular therapeutic use. However, a synergism of penicillins with drugs acting similarly on the complement system, such as iodinated radiographic contrast media, may be expected.

Azlocillin↗
PubMed2005

The role of complement in immunological demyelination of the mammalian spinal cord.

STUDY DESIGN: Specificity of serum complement component to elicit immunological demyelination. OBJECTIVES: To assess the role of complement components and pathways in experimental immunological demyelination of the adult rat spinal cord. SETTING: ICORD, University of British Columbia, Vancouver, Canada. SUBJECTS: We used 32 adult male Sprague-Dawley rats, of approximately 220 g weight. METHODS: Rats received intraspinal infusions of demyelinating reagents, delivered by osmotic minipump, for a 7-day infusion at 0.5 microl/h. Reagents consisted of a polyclonal antibody to galactocerebroside and human serum complement. Complement sera deficient for a single component were used to assess the role of the alternative pathway, the classical pathway, and the membrane attack complex. Demyelination was assessed, at 7 days, ultrastructurally. RESULTS: Removal of C3 protein, common to classical and alternative complement pathways, or C4 protein, a classical pathway protein, resulted in no demyelination. However, complement deficient in Factor B, an alternative pathway protein, produced effective demyelination. Upon removal of C5 or C6, membrane attack complex proteins, demyelination was also observed. CONCLUSION: This suggests that the classical pathway is sufficient for the protocol to demyelinate the adult rat spinal cord, and that the membrane attack complex is also not required.

Animals↗